Neural tube defects (NTDs) are common, serious malformations that are associated with both excess morbidity and mortality. Although there are several known causes of NTDs, a specific etiologic agent(s) cannot be identified in the majority of cases. Maternal proximity to hazardous waste sites and exposure to pesticides have both been implicated as, but are not considered to be established risk factors for NTDs in offspring. Definitive conclusions regarding the association between these, and other environmental exposures and NTD risk have been hampered by the rarity of this outcome (<1/1000 births), differences in exposure assessment between studies, and overly simplistic etiological models. The studies proposed in this application are designed to minimize these limitations while addressing the primary study hypothesis: maternal exposure to polycyclic aromatic hydrocarbons and inorganic arsenic contributes to the risk of NTDs in offspring, and the effects of these environmental exposures are modified by nutritional and genetic factors. In our evaluation of this hypothesis we will consider the possibility that the interplay of environmental and genetic risk factors may be more relevant to the risk of NTDs than is the independent main effect of any single factor. In addition, we will consider both the maternal and the embryonic genotypes as potential modifiers of the association between maternal exposures and risk of NTDs in offspring.